We have a long-standing interest in the genetics, molecular and cellular biology of neurodegenerative disorders. Our aim is to unravel the physiological and pathogenetic function of key genes and mechanisms which underly and drive the processes causing dementia. For this we use Alzheimer's disease (AD) as a model. This disease is the most common human neurodegenerative disorder afflicting 1,4 percent of the population in the Western world. Its most characteristic molecular and cellular hallmarks are the accumulations of intraneuronal Aβ peptides and extracellular deposits of this Aβ peptide (Fig. 1) which are the cause of synaptic dysfunction and neuronal loss. Aβ is a 40-43 amino acid fragment, formed from neuronal amyloid precursor protein (APP) by two sequential proteolytic cleavage events. The first cleavage takes place within the ectodomain of APP and is mediated by β-secretase (BACE). The second cleavage generates the C-terminus of Aβ and occurs within the transmembrane domain of APP by three consecutive cleavages termed ε-, ζ- and γ-cleavage which are all mediated by the γ-secretase complex. In order to understand better the mechanism of this second cleavage within the lipid bilayer, we initiated experiments designed to unravel the mechanism of this process by expressing APP molecules carrying mutations altering the length of its transmembrane domain or allowing to introduce charged groups into it. Together with Stefan Lichtenthaler, Beate Grziwa, and Tobias Hartmann in our lab, this approach led to the first experimental demonstration that the site at which γ-secretase cleaves is the middle of the lipid bilayer.